DESCRIPTION: (Applicant's Abstract) The transplantation of cells or tissue into the CNS is a potential means of achieving sustained delivery of naturally derived pharmacologically active substances for the alleviation of chronic disorders. Work in our laboratory has demonstrated that adrenal medullary or chromaffin cell transplants in the spinal subarachnoid space can alleviate pain symptoms in several animal models. This most likely involves the release of pain-reducing neuroactive substances, such as opioid peptides and catecholamines, from the transplanted cells. A significant advantage of the transplant approach for the chronic pain patient is the potential ability to provide a continually renewable source of analgesic agents, reducing or eliminating the need for repeated narcotic administration. As a result of promising findings in animal studies, clinical studies have been initiated at several centers in patients with cancer pain, with encouraging results. The goals of the proposed studies are to understand the mechanisms, long-term consequences, and potential limitations of these transplants in the CNS. Pharmacologic and biochemical analyses will be done in order to determine transplant interactions with host spinal receptors, the contribution of opioid and other neuropeptides to pain reduction, and tolerance and cross-tolerance to traditional pharmacotherapies. The mechanisms of the transplants in reducing both acute and chronic pain processes may be distinct, and will be evaluated using selective nociceptor activation and acute and chronic pain models. It is thought that chronic pain such as that consequent to peripheral nerve injury or inflammation results from a cascade of neuropathological events leading to persistent hyperexcitability, including activation of NMDA receptors and the production of nitric oxide and cyclic GMP. Clinically, in spite of advances in pain management, some of the most debilitating disorders are those associated with peripheral or central nerve lesions and chronic inflammation, and are poorly or inadequately controlled by traditional pharmacotherapies. Recent studies in our laboratory have suggested that adrenal medullary or chromaffin cell transplants can alleviate symptoms of chronic pain due to peripheral nerve injury and inflammation, and may do so via intervening in the NMDA/NO cascade. Thus, if successful, the findings from these studies could lead to a novel approach in the long term therapeutic intervention for alleviation of chronic pain syndromes, particularly those refractory to traditional pharmacotherapies, who would benefit greatly by improved quality of life free from pain.